The hepatitis B virus belongs to the family of hepadna viruses. It can cause acute and/or persistent or progressive chronic diseases. Many other clinical manifestations in the pathological state are also caused by the hepatitis B virus—in particular chronic inflammation of the liver, cirrhosis of the liver and hepatocellular carcinoma. In addition, coinfection with the heptatitis delta virus may have adverse effects on the progress of the disease.
The interferon and lamivudine are conventional medicaments approved to be used for treating chronic hepatitis. However, the interferon has just moderate activity but has an adverse side reaction. Although lamivudine has good activity, its resistance develops rapidly during the treatment and relapse effects often appear after the treatment is stopped. The IC50 value of lamivudine (3-TC) is 300 nM (Science, 299 (2003), 893-896).
U.S. Pat. No. 7,074,784 discloses 6-amidoalkyldihydropyrimidine and its use as a medicament especially for treating and preventing hepatitis B infection.
It is described in Example 12 of U.S. Pat. No. 7,074,784 that R1 is o-chlorine, R2 is p-chlorine, R6 is 3,5-difluoro-pyridin-2-yl, X is —CH2— and Z is morpholinyl. The compound can inhibit the growth of hepatitis B virus during cell culturing. The IC50 value is 2 nM (tested by themselves).
The main substitution in Example 12 is replacing bis-chlorine with R1 (o-bromine) and R2 (p-fluorine), which results in the IC50 of Compound 9 being 7 nM (described in Example 9 of the patent). And when the main substituents are changed into R1 (o-chlorine) and R2 (p-fluorine), an approximate IC50 value is also obtained (IC50=2-4 nM in Example 5).
It is indicated that the IC50 value cannot increase with the variation of the main substituents R1 and R2 (see Table 1).
U.S. Pat. No. 7,074,784 B2 also discloses an example, wherein a difluoro residue is substituted for thiazol-2-yl (described in Example 45 of the patent). The derivative has a similar IC50 value (2 nM) (see Table 1).
TABLE 1Example 2 of U.S. Pat. No. 7,074,784 B2ExampleR1R2R3R6IC50 (nM)12ClClCH32 (self-tested)  9BrFCH37  5ClFCH32-4 45ClClCH32